Abstract
Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE) can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR) regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane-induced learning and memory disability via the PPAR signaling pathway. Six-day-old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6) to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-γ expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-γ expression. Both EE and the PPAR-γ agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signaling pathway. PPAR-γ may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity.
Highlights
Pediatric patients who undergo multiple surgeries require multiple exposures to general anesthesia
Children who are frequently exposed to general anesthesia and surgery at an early age may develop impairments in learning and memory [1]
Mice were treated daily with 3% sevoflurane for 2 h from postnatal day 6 (P6) to P8, after which they were tested in the Morris Water Maze (MWM) from P30 to P34
Summary
Pediatric patients who undergo multiple surgeries require multiple exposures to general anesthesia. Sevoflurane is the most widely used inhaled anesthetic for general anesthesia in children. Recent studies showed that children with multiple exposures to general anesthesia and surgery at an early age may develop learning and memory disabilities [1, 2]. Sevoflurane has been shown to inhibit the proliferation of neural progenitor cells, decrease the selfrenewal capacity of neural stem cells, and induce neuroinflammation in microglial cells in mice [3,4,5,6]. Results from animal studies showed that multiple exposures of sevoflurane may induce neuroinflammation, neuronal apoptosis, and neurogenesis inhibition in the brain tissues of 6-day-old fetal mice. Sevoflurane-induced neurotoxicity in the developing brain is drawing more attention in the context of children who are exposed to inhalational general anesthetics for surgery
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